Intensified Conditioning Regimen With High-Dose-Etoposide for Allo-HSCT for Adult Acute Lymphoblastic Leukemia

Evolving paradigms in the treatment of adult ALL include the application of intense pediatric regimens to the treatment of adolescents and young adults (AYA) and the optimization of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the cure of patients. The Cancer and Leukemia Group B (CALGB) and the Children's Cancer Group (CCG) first asked whether AYA between the ages of 16 and 20 fared differently whether they were treated on pediatric protocols. The results of this study demonstrated that although the complete remission rates were identical for the AYAs treated on the CALGB and CCG trials, the AYAs had a 63% event-free survival (EFS) and 67% OS at 7 years on the CCG trials compared with 34% and 46%, respectively, on the CALGB trials.

High relapse and transplantation-related-mortality still remains great challenge for HSCT of adult ALL, which both range between 25% and 30%. Recently, risk-adapted indication and optimization of conditioning regimen are highlighted, which aiming to reduce TRM and relapse rate, respectively.City of Hope National Medical Center studied the substitution of etoposide (VP-16) for CY in the treatment of ALL patients receiving HCT. The result suggested that etoposide and TBI are associated with a decreased relapse rate following transplantation for ALL, compared with those receiving CY and TBI. Japanese and Germany reports pronounced the advantage of VP-16 in intensified regimen for adult ALL. On the same time, the investigators previous researches have confirmed the effect and safety of FA-intensified conditioning regimen on relapse and refractary leukemia.

Based on mentioned above, the investigators speculate that VP-16-intensified conditioning regimen could improve the outcome for adult ALL. The potential mechanism will be attributed to reduce MRD and promote GVL effect via providing enough time-window for immuno-reconstitution by high-dose preparative regimen.

In the first decade of the new millennium, multiple studies have begun to change our thinking about the treatment of adults with acute lymphoblastic leukemia (ALL). In pediatric patients cure rates in the range of 80% to 90% are now attainable. While adult patients with ALL now have a 90% complete remission (CR) with modern chemotherapy, most patients will relapse, and leukemia-free survival with 3 to 7 years of follow-up in large series is only in the range of 30% to 40%. The poor outcome of chemotherapy in adults with ALL as compared to children relates to multiple factors, including poor tolerance of intensive courses of chemotherapy and a higher incidence of poor prognostic subtypes of ALL such as Philadelphia chromosome-positive ALL and a lower incidence of favorable subtypes such as the t (12; 21).

Evolving paradigms in the treatment of adult ALL include the application of intense pediatric regimens to the treatment of adolescents and young adults (AYA) and the optimization of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the cure of patients. Adult regimens are typically less intense than pediatric regimens. The Cancer and Leukemia Group B (CALGB) and the Children's Cancer Group (CCG) first asked whether AYA between the ages of 16 and 20 fared differently whether they were treated on pediatric protocols. The results of this study demonstrated that although the complete remission rates were identical for the AYAs treated on the CALGB and CCG trials, the AYAs had a 63% event-free survival (EFS) and 67% OS at 7 years on the CCG trials compared with 34% and 46%, respectively, on the CALGB trials. These results have prompted new studies where pediatric ALL regimens have been adapted to the treatment of younger adults. With short follow-up, GRAALL-2003 reports suggest EFS and OS outcomes in the range of 60%. This improved outcome was more pronounced in the standard-risk patients with a donor who had an OS at 5 years of 69%. On the same time, our previous researches have confirmed the effect and safety of FA-intensified conditioning regimen on relapse and refractary leukemia.

Based on mentioned above, we speculate that VP-16-intensified conditioning regimen could improve the outcome for adult ALL. The potential mechanism will be attributed to reduce MRD and promote GVL effect via providing enough time-window for immuno-reconstitution by high-dose preparative regimen.

• Acute Lymphoblastic Leukemia
• Stem Cell Transplantation, Hematopoietic

• Other: TBI/CY/VP-16
  CR1 Cohort will receive condition regimen of TBI/CY/VP-16: TBI: 4.5Gy/d, -5d, -4d; CY: 60mg/kg/d, -3d, -2d; VP-16: 15mg/kg/d, -2d, -1d
• Other: FA-TBI/CY/VP-16
  Non-CR1 Cohort will receive conditioning regimen of FA-TBI/CY/VP-16: Flu: 35mg/m2/d: -10->-6d; AraC: 1g/m2/d, -10d->-6d; TBI: 4.5Gy/d, -5d,-4d; CY:60mg/kg/d, -3d, -2d; VP-16: 15mg/kg, -2d, -1d

• Experimental: First Complete Remission of ALL
  CR1 Cohort: subject with ALL in First Complete Remission (CR)
  Intervention: Other: TBI/CY/VP-16
• Experimental: Non-First Complete Remission
  Non-CR1 Cohort: subject with ALL beyond first CR, or not remission
  Intervention: Other: FA-TBI/CY/VP-16

• Liu QF, Fan ZP, Zhang Y, Jiang ZJ, Wang CY, Xu D, Sun J, Xiao Y, Tan H. Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia. Biol Blood Marrow Transplant. 2009 Nov;15(11):1376-85. Epub 2009 Aug 19.
• Ottmann OG, Pfeifer H. Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Hematology Am Soc Hematol Educ Program. 2009;:371-81.
• Laport GG, Alvarnas JC, Palmer JM, Snyder DS, Slovak ML, Cherry AM, Wong RM, Negrin RS, Blume KG, Forman SJ. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood. 2008 Aug 1;112(3):903-9. Epub 2008 Jun 2.
• Seibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: peaks and pitfalls. Hematology Am Soc Hematol Educ Program. 2008;:374-80. Review.
• Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. Review. No abstract available.
• Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801.
• Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH. Induction therapy for adults with acute lymphoblastic leukemia (ALL): results of over 1,500 patients from the international ALL Trial: MRC UKALL XII / ECOG E2993. Blood. 2005 Aug 16; [Epub ahead of print]
• Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia (ALL) the greatest benefit is achieved from a matched sibling allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy in All patients : final results of the international ALL trial (MRC UKALL XII/ ECOG E2993). Blood. 2007 Nov 29; [Epub ahead of print]
• Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009 Feb 20;27(6):911-8. Epub 2009 Jan 5. Erratum in: J Clin Oncol. 2009 May 20;27(15):2574. Dosage error in article text.
• Marks DI, Forman SJ, Blume KG, Pérez WS, Weisdorf DJ, Keating A, Gale RP, Cairo MS, Copelan EA, Horan JT, Lazarus HM, Litzow MR, McCarthy PL, Schultz KR, Smith DD, Trigg ME, Zhang MJ, Horowitz MM. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006 Apr;12(4):438-53.

Inclusion Criteria:

1. Age: 16 years to 65 years
2. Diagnosis of acute lymphoblastic leukemia
3. Disease condition in CR1 or Non-CR1
4. Patient received allogeneic hematopoietic stem cell transplantation
5. The informed consent form has been signed.
6. The following exclusion criteria are excluded.

Exclusion Criteria:

1. Patient with severe cardiac dysfunction with less than 50% EF
2. Patient with severe lung dysfunction
3. Patient with severe hepatic or renal dysfunction with more than 3 times the upper limit of normal range (ULN) of serum ALT or AST levels, or with more than 2 times the upper limit of normal range (ULN) of serum TBIL level or less than 40% of normal prothrombin time activity (PTA); or with more than 2 times the ULN of serum Cr
4. Patient with severe active infection
5. Patient with allergy history about suspected drug in conditioning regimen
6. Patient with other conditions considered unsuitable for the study